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by the BSB, replicating these conditions in preclinical settings requires athorough understanding of ECM composition and cell-ECM interactions.The dense ECM found in the majority of solid tumors combined withabnormal vasculature leads to poorly perfused regions where metabolitesand reactive oxygen species (ROS) accumulate, while oxygen levels areseverely depleted. When tumors develop hypoxic regions, they adapt theirmetabolism to survive in this oxygen-depleted microenvironment. Thesemetabolic adaptations affect essential cellular functions, includingendocytic receptor internalization, energy metabolism, intracellulartrafficking, signaling, and transmembrane receptor recycling. Such changescontribute to enhanced multidrug resistance mechanisms. Endocytosis andproper intracellular trafficking are critical for the effective delivery oftherapeutic payloads in cancer nanomedicines. However, since theendocytic uptake of nanomedicines is energy-dependent, hypoxia-inducedalterations can directly undermine nanomedicine efficacy. Finally, beyondserving as a physical barrier, the ECM influences cell signaling pathways,promoting tumor progression and resistance to therapy.3.3. Impact of Cellular heterogeneity on Nanotherapeutics efficacyFrom the process of extravasation and tissue penetration to tumor celltargeting and accumulation, nanotherapeutics inevitably interact with thesurrounding non-cancerous cell populations within the TME. The influenceof these distinct cellular populations on the efficacy and delivery ofnanotherapeutics is directly associated with the specific therapeutic beingemployed. The activated stromal components of the TME, which areprimarily responsible for modifying the tumor ECM, frequently act asbarriers to therapeutic delivery. Conversely, other stromal cells, such asmesenchymal stromal cells, may facilitate tumor resistance andproliferation or, more significantly, regulate immune cell responses. Immunecells present within the TME can exert profound effects on the efficacy andmechanisms of action of nanomedicines.Since its introduction in the late 1990s, cancer nanomedicine hasprimarily focused on the development of drug delivery systems designed toevade immune detection and deliver therapeutic agents directly to tumorcells. However, as previously discussed, it is now recognized that the designof nanomedicines to actively engage the immune system and induce antitumoral responses presents considerable potential for cancer treatment.The use of nanotherapeutics for immuno-oncological purposes necessitatesnano-formulations capable of precisely modulating the adaptive and/orinnate immune system. For instance, immune cells within the TME, such as111 Nanomaterial y NanomedicinaMar%u00eda Vallet , Antonio J. Salinas